• A Corrigendum to this article was published on 23 March 2018

This article has been updated

Abstract

A large proportion of biomedical research and the development of therapeutics is focused on a small fraction of the human genome. In a strategic effort to map the knowledge gaps around proteins encoded by the human genome and to promote the exploration of currently understudied, but potentially druggable, proteins, the US National Institutes of Health launched the Illuminating the Druggable Genome (IDG) initiative in 2014. In this article, we discuss how the systematic collection and processing of a wide array of genomic, proteomic, chemical and disease-related resource data by the IDG Knowledge Management Center have enabled the development of evidence-based criteria for tracking the target development level (TDL) of human proteins, which indicates a substantial knowledge deficit for approximately one out of three proteins in the human proteome. We then present spotlights on the TDL categories as well as key drug target classes, including G protein-coupled receptors, protein kinases and ion channels, which illustrate the nature of the unexplored opportunities for biomedical research and therapeutic development.

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Change history

  • 23 March 2018

    In the version of this article that was originally published online, an older version of the data set categorizing proteins into target development levels was used to create Figure 1 than the version used to create Table 1, and data from Figure 1 were referred to at several points in the text of the article. Figure 1 and the associated text have been updated to match Table 1 in the online and print versions of the article. The authors apologize for any inconvenience that this error may have caused.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants U54 CA189205 and U24 224370 (Illuminating the Druggable Genome Knowledge Management Center (IDG KMC)) at the University of New Mexico, Novo Nordisk Foundation Center for Protein Research, European Bioinformatics Institute (EBI) and University of Miami, U54 CA189201 and U24 CA224260 (A.M., Mount Sinai), P30 CA118100 (T.I.O., G.N.G. and L.A.S., UNM) and UL1 TR001449 (T.I.O. and L.A.S.), UM1 HG006370 (International Mouse Phenotyping Consortium, T.F.M. and I.T.), U01 MH104974 (B.L.R.), U01 MH104984 (S.T.), U01 MH105028 (M.T.M.), U01 MH105026 (J.Q. and A.M., Baylor) and U01 MH104999, R01 CA177993 and U24 DK116204 (S.G. and G.L.J.) and by the European Molecular Biology Laboratory (EMBL) and Wellcome Trust Strategic Awards WT086151/Z/08/Z and WT104104/Z/14/Z (A.G., A.H., A.R.L., A.K., J.P.O., and G.P.); and by Novo Nordisk Foundation Denmark grant NNF14CC0001 (S.B., L.J.L. and D.W). R.G., A.J., D.T.N., A.S., N.S., and G.Z.K. were supported by the Intramural Research Program, National Center for Advancing Translational Sciences (NCATS) and by U54 CA189205. Dedicated to Francisc Schneider (1933–2017).

Author information

Author notes

    • Anneli Karlson

    Present addresses: SciBite Limited, BioData Innovation Centre, Wellcome Genome Campus, Hinxton, Cambridge, UK.

Affiliations

  1. Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.

    • Tudor I. Oprea
    • , Cristian G. Bologa
    • , Jayme Holmes
    • , Subramani Mani
    • , Stephen L. Mathias
    • , Oleg Ursu
    • , Jeremy J. Yang
    •  & Gergely Zahoránszky-Köhalmi
  2. UNM Comprehensive Cancer Center, Albuquerque, NM, USA.

    • Tudor I. Oprea
    • , Gregory N. Gan
    •  & Larry A. Sklar
  3. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

    • Tudor I. Oprea
  4. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Tudor I. Oprea
    • , Søren Brunak
    • , Lars Juhl Jensen
    •  & David Westergaard
  5. IQVIA, Plymouth Meeting, PA, USA.

    • Allen Campbell
  6. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK.

    • Anna Gaulton
    • , Anne Hersey
    • , Anneli Karlson
    • , Andrew R. Leach
    • , Terrence F. Meehan
    • , John P. Overington
    • , George Papadatos
    •  & Ilinca Tudose
  7. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC, USA.

    • Shawn M. Gomez
  8. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

    • Shawn M. Gomez
    • , Gary L. Johnson
    •  & Bryan L. Roth
  9. National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, USA.

    • Rajarshi Guha
    • , Ajit Jadhav
    • , Dac-Trung Nguyen
    • , Anton Simeonov
    •  & Noel Southall
  10. Icahn School of Medicine at Mount Sinai, New York, NY, USA.

    • Avi Ma'ayan
  11. Baylor College of Medicine, Houston, TX, USA.

    • Anna Malovannaya
    •  & Jun Qin
  12. University of California, San Francisco, CA, USA.

    • Michael T. McManus
  13. Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.

    • Christian von Mering
  14. Respiratory, Inflammation and Autoimmunity Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.

    • Daniel Muthas
  15. IQVIA, Cambridge, MA, USA.

    • Christian Reich
  16. Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, USA.

    • Stephan C. Schürer
    •  & Dušica Vidović
  17. Center for Molecular Discovery, University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM, USA.

    • Larry A. Sklar
    •  & Anna Waller
  18. Department of Pathology, University of New Mexico, Albuquerque, NM, USA.

    • Larry A. Sklar
  19. Yale School of Medicine, Yale University, New Haven, CT, USA.

    • Susumu Tomita
  20. Medicines Discovery Catapult, Alderley Edge, UK.

    • John P. Overington
  21. GlaxoSmithKline, Stevenage, UK.

    • George Papadatos
  22. Google Germany GmbH, München, Germany.

    • Ilinca Tudose
  23. NIH-NCATS, Rockville, MD, USA.

    • Gergely Zahoránszky-Köhalmi

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Competing interests

S.B. and L.J.J. are co-founders, shareholders and scientific advisory board members of Intomics A/S, an omics data integration company. A.C. and C.R. are employees of IQVIA, a company serving the combined industries of health information technologies and clinical research. I.T. is a current employee of Google Germany. G.P. is a current employee of GlaxoSmithKline, a global health-care company. D.M. is a current employee of AstraZeneca, a global, research-based biopharmaceutical company. J.P.O. is currently an employee of Medicines Discovery Catapult, a UK government-funded facility for collaborative research and development.

Corresponding author

Correspondence to Tudor I. Oprea.

Supplementary information

PDF files

  1. 1.

    Supplementary Box S1

    Context, time and knowledge management

  2. 2.

    Supplementary File S2

    Plot of bioactivity values for major target classes.

  3. 3.

    Supplementary S4 table

    Statistical significance results for the four validating metrics shown in Figure 2a

  4. 4.

    Supplementary S5 Box

    Spotlight on the ionizing radiation proteome

  5. 5.

    Supplementary S7 table

    Spotlight on selectivity

  6. 6.

    Supplementary File S11

    IMS Health (MIDAS) global drug sales data (2011-2015), organized by ATC level 2 codes and by protein class, normalized to percentage values.

Excel files

  1. 1.

    Supplementary Information

    Supplementary S3 table

  2. 2.

    Supplementary information

    Supplementary S8 table

  3. 3.

    Supplementary information

    Supplementary S9 table

  4. 4.

    Supplementary information

    Supplementary S10 table

  5. 5.

    Supplementary information

    Supplementary S11 table

Glossary

Drug

Externally administered, possibly endogenous but mostly xenobiotic, substances that are administered to patients in order to influence the outcome of a disease, syndrome or condition.

Drug targets

Molecular entities present in living systems that, upon interaction with therapeutic agents or their by-products, result in modified biological responses that lead to therapeutic outcomes. The interaction between a drug and its target leads, directly or indirectly, to observable clinical outcomes.

Druggable genome

Originally defined by Hopkins and Groom as the set of genes that encode proteins that could be modulated by an orally administered small molecule, as estimated by Lipinski's 'rule of five' guidelines.

Mode of action

Referred to as 'mechanism of action' when the molecular interactions are well understood; describes the way in which drugs exert their intended therapeutic action, resulting in the intended therapeutic outcome.

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DOI

https://doi.org/10.1038/nrd.2018.14

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